a-Synuclein (a-Syn) is a key protein in the pathogenesis of Parkinson's disease (PD) and other a- synucleinopathies. Postmortem investigations have demonstrated fibrillar a-Syn aggregates in Lewy bodies and Lewy neurites in affected brain regions in these disorders. A critical factor in the pathologic aggregation of this protein appears to be its intraneuronal concentration. Besides the fact that multiplication of the a-Syn gene locus is linked to dominantly inherited PD with an onset age that correlates inversely with gene dosage, transgenic animal models expressing wild-type human a-Syn manifest phenotypic changes reminiscent of this disease, and various cellular models in culture are made vulnerable to oxidative insults by over-expressing this protein. All these observations collectively indicate that over-expression of a-Syn is deleterious to neurons and particularly to nigral dopaminergic neurons. microRNA (miRNA) is a small (19- 24 nt) endogenous non-coding RNA which binds to the 3'-untranslational region (UTR) of mRNA in a sequence-specific manner, thereby suppressing expression of target genes. Recently, we found that miRNA-7 (miR-7) represses a-Syn protein level by targeting the 3'-UTR of this transcript. Further, miR-7- induced down-regulation of a-Syn protects cells against oxidative stress in cellular models. This application proposes to investigate the function of miRNAs including miR-7 in the pathogenesis of PD in relation to a- Syn regulation. We hypothesize that certain miRNAs repress a-Syn expression in vivo and that dysfunction of specific miRNA species results in loss of this check mechanism in disease states, leading to increased a- Syn expression and ultimately neurodegeneration. Both cellular and mouse models will be employed to carry out these investigations. Since inhibitors of a-Syn expression are attractive therapeutic targets for PD and other a-synucleinopathies, detailed understanding of these mechanisms provides potential new therapeutic approaches to slow or halt PD progression. PUBLIC HEALTH RELEVANCE: Parkinson's disease and related progressive disorders of the brain have abnormal accumulation of a protein called alpha-synuclein in brain cells. The amount of this protein is critical in promoting its accumulation, which is believed to be harmful to these cells. Therefore, learning what controls the amount of this protein will help devise new treatments of these diseases. This project will study a new mechanism that controls alpha-synuclein levels.